1. Field of the Invention
This invention relates generally to pharmaceutical formulations and, in particular, to an antioxidant stabilizer system for pharmaceutical formulations containing compounds such as isoxazole derivatives used for the treatment of Irritable Bowel System (IBS).
2. Description of Related Art
Pharmaceutical formulations are made using materials such as antibiotics, antacids, drugs and vitamins and are prepared in a variety of forms including tablets, capsules, ointments, liquids, etc. An overriding problem with any pharmaceutical formulation, however, is the stability of the active ingredient. Stability generally relates to loss of potency but loss of potency may also be accompanied by the formation of by-product materials which are harmful from a health standpoint.
Irritable Bowel Syndrome (IBS) is a motor disorder consisting of altered bowl habits, abdominal pain, and the absence of detectable pathology. IBS is recognized by its symptoms, which are markedly influenced by psychological factors and stressful life situations.
IBS is one of the most commonly encountered gastrointestinal disorders. Between 20% and 50% of patients referred to gastrointestinal clinics suffer from IBS. Symptoms of IBS occur in approximately 14% of otherwise apparently healthy people. It is one of the least understood disorders, in part because it is not a disease but a syndrome composed of a number of conditions with similar manifestations. The major symptoms of IBS (altered bowel habits, abdominal pain and bloating) are manifestations of increased motility in the gut and hyper-secretion of gastric acid.
Current treatment for IBS include pharmaceutical formulations containing compounds that are both direct acting 5-HTIA agonists and M1-cholinergicxe2x80x94receptor selective agents. Since these two characteristics are important to normalize the bowel habits and reduce the abdominal pain and distension of IBS, these agents which have this combination of activities act to normalize gastrointestinal motility and, be useful in the treatment of IBS conditions.
Pharmaceutical formulations and a method for testing IBS in mammals including humans are shown in U.S. Pat. No. 5,434,174, which patent is incorporated herein by reference. The method comprises administering to a mammal in need of IBS treatment, an effective dose of a compound of the formula I. 
wherein:
R is hydrogen, C1-C3 alkyl, allyl, or 
R1 is hydrogen, C1-C3 alkyl, allyl, 
xe2x80x83or xe2x80x94(CH2)nxe2x80x94x;
n is to 1 to 5;
X is an optionally substituted phenyl, C1-C3 alkoxy, or C1-C3 alkylthio;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halo, CN, or phenyl; or together are xe2x80x94(CH2)pxe2x80x94;
p is 3 to 6;
Y is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SOxe2x80x94m;
m is 0,1, or 2;
or a pharmaceutically acceptable acid addition salt or solvate thereof.
The ""174 patent also discloses pharmaceutical formulations adapted for the treatment of IBS comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient therefor.
Unfortunately, pharmaceutical formulations made using materials corresponding to compound I and other materials containing oxidizable groups are relatively unstable during storage and lose their potency over time. This, of course, is not acceptable and pharmaceutical formulations having increased storage stability are highly desired.
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a chemically stable pharmaceutical composition comprising therapeutically effective amounts of materials corresponding to a compound of formula I.
It is another object of the present invention to provide a method for treating IBS in humans by administering to the humans in need of treatment an effective dose of a stable pharmaceutical composition containing therapeutical amounts of materials corresponding to a compound of formula I.
Another object of the invention is to provide a stabilizer system for materials corresponding to the compound of formula I.
A further object of the invention is to provide a stabilizer system for pharmaceutical formulations containing materials having oxidizable groups such as amino, phenolic, hydroxyl amino, aldehyde, unsaturated compounds such as alkenes, isoxazole, sulfoxide, sulfone and mercapto and chemically stable pharmaceutical formulations containing the stabilizer system.
Other objects and advantages of the present invention will be readily apparent from the following description.
The above and other objects and advantages, which will be apparent to one of skill in the art, are achieved in the present invention which is directed, in a first aspect, to a chemically stable pharmaceutical composition comprising:
a therapeutically effective amount of a material corresponding to a compound of formula I; 
xe2x80x83wherein:
R is hydrogen, C1-C3 alkyl, allyl, or 
R1 is hydrogen, C1-C3 alkyl, allyl, 
xe2x80x83or xe2x80x94(CH2)nxe2x80x94x;
n is to 1 to 5;
X is an optionally substituted phenyl, C1-C3 alkoxy, or C1-C3 alkylthio;
R2 and R3 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halo, CN, or phenyl; or together are xe2x80x94(CH2)pxe2x80x94;
p is 3 to 6;
Y is xe2x80x94CH2xe2x80x94,xe2x80x94Oxe2x80x94, xe2x80x94SOxe2x80x94m;
m is 0,1, or 2;
or a pharmaceutically acceptable acid addition salt or solvate thereof;
an organic carboxylic acid containing more than 1 carboxylic acid group preferably 2 acid groups; and
an antioxidant or mixture of antioxidants.
In another aspect of the invention, a method of treating IBS in mammals including humans comprises administering to the mammal in a need of treatment an effective dose of a chemically stable pharmaceutical composition comprising:
a therapeutically effective amount of a material corresponding to a compound of formula I or a pharmaceutically acceptable acid addition salt or solvate thereof;
an organic carboxylic acid containing more than 1 carboxylic acid group preferably 2 acid groups; and
an antioxidant or mixture of antioxidants.
In a further aspect of the invention, a stabilizer system is provided for pharmaceutical compositions including pharmaceutical compositions comprising a therapeutical amount of a material corresponding to a compound of formula I comprising:
an organic carboxylic acid containing more than 1 carboxylic acid group preferably 2 acid groups; and
an antioxidant or mixture of antioxidants.
In an additional aspect of the invention, a chemically stable pharmaceutical formulation and a method of treating mammals with the chemically stable pharmaceutical formulation are provided wherein the stabilizer system comprises:
an organic carboxylic acid containing more than 1 carboxylic acid group preferably 2 acid groups; and
an antioxidant or mixture of antioxidants.
In an additional aspect of the invention, the organic carboxylic acid material containing more than 1 carboxylic group is a dicarboxylic acid and preferably a hydroxy dicarboxylic acid and most preferably an xcex1-hydroxy dicarboxylic acid such as citric acid and tartaric acid. The organic carboxylic acid is admixed with an antioxidant such as the preferred ascorbic acid and a substituted phenol such as butylated hydroxytoluene (BHT). A single antioxidant may be used with the carboxylic acid material but preferably a mixture of antioxidants such as ascorbic acid and derivatives such as ascorbyl palmitate and BHT are used in admixture with the carboxylic acid. The pharmaceutical formulations may contain any of the pharmaceutically accepted carriers, diluents or excipients as is well known in the art.